Block copolymer

ABSTRACT

Cross-linked block copolymers are disclosed which have drug retention properties, comprising hard and soft segments, with cross-linking between the soft segments. The block copolymers can be based upon (meth)acrylic monomers, and some possess adhesive properties.

RELATED APPLICATIONS

This application claims priority from application 9714650.0 which wasfiled in the United Kingdom on Jul. 11, 1997.

The present invention relates to block copolymers useful in transdermalpatches as adhesives and/or drug retention means, as well as totransdermal patches comprising such block copolymers.

Transdermal patches are well known in the pharmaceutical industry andare used to deliver drugs into the skin of a patient. Drug delivery byuse of a transdermal patch has a number of advantages over oral deliverymethods. For example, the drug may be provided continuously over a longperiod, rather than in spaced apart, higher doses, and the patches areeasy to apply and use.

The patch must have an adhesive portion, to allow the patch to adhere tothe skin. An adhesive suitable for use in a transdermal patch shouldpossess certain properties, including adhesion, tack and cohesion.Adhesion refers to the force with which the adhesive sticks to asurface. Tack refers to the speed at which the adhesive can form a bondwith the surface, while cohesion refers to the internal strength of anadhesive and its ability to resist splitting when placed under externalstress. Good cohesion, in particular, is necessary for clean removal ofthe transdermal patch.

A primary use of the adhesive may be to affix a patch to the skin.However, it is preferable for the drug to be delivered to beincorporated into the adhesive, where possible, in order to reduce theamount of components and, therefore, expense necessary to make thepatch.

A number of adhesives are already available for se in transdermalpatches. Acrylic polymers are commonly used, as these possess adhesiveproperties which may easily be modulated by changing the composition ofthe polymer.

In connection with transdermal patches, U.S. Pat. No. 5,413,776discloses the use of a copolymer adhesive consisting of an acrylic acidester polymer portion in combination with an N-vinyl-2 pyrrolidonepolymeric portion. EP-A-450986 discloses the use of an alkylmethacrylate (co)polymer in combination with silicic acid anhydride,specifically for the delivery of nicotine. Both adhesives are acryliccopolymers.

EP-A-0450986 further discloses that a multi-functional monomer may beincluded as a copolymer, to provide chemical cross-links between thecopolymer strands. Chemical cross-linking is thought to increase thedegree of polymerisation and, thus, cohesion of the adhesive.

Block copolymers have also been used as adhesives for transdermalpatches. A block copolymer consists of a mixture of ‘hard’ (A) and‘soft’ (B) segments, which may be combined in an A-B-A or (A-B)_(n) typestructure (c.f. Block Copolymers: Overview and Critical Survey, Noshayand McGrath, 1977). Association of the hard segments is thought toprovide a degree of physical cross-linking, which improves the cohesiveproperties of the adhesive. One such example of a block copolymeradhesive is a polystyrene-polyisoprene-polystyrene (SIS) which is anA-B-A type block copolymer adhesive made by Shell, for example. Thisadhesive requires the use of an additional tackifier to provide suitabletack to the adhesive.

U.S. Pat. No. 5,066,728 discloses a multiblock copolymer comprisingendblocks of phenylbutadiene and an elastomeric midblock of a conjugateddiene such as isoprene or butadiene. The copolymer is cross-linkable byelectron beam radiation, such that the crosslinks are confined primarilyto the end-block domains in the polymer, with minimal crosslinkingoccurring in the rubbery matrix. Blends of the copolymer with tackifierresins provide curable pressure sensitive adhesives.

JP-62036412A discloses vinyl chloride resins, produced by a graftcopolymerisation of vinyl chloride and a block copolymer, wherein thecopolymer contains a soft segment that is crosslinked. The resinsreportedly have a excellent impact resistance, weather-proofingproperties and bending elasticity.

WO-97/01589 also discloses graft copolymers, suitable for use ininfluencing optical quality, dyeabilty, stability to weather or impactcracking and stress cracking in moulding compositions. The graftcopolymers comprise a soft segment with at least one acrylate monomer,and a hard segment comprising at least one vinyl aromatic monomer. Thesoft segment is cross-linked, and the hard and soft segments areoverlaid.

While a number of adhesives are available for use in transdermalpatches, there is still a need for transdermal patch adhesives whichpossess excellent tack, cohesion and improved drug storage capacity.

It has now, surprisingly, been found that a degree of chemicalcross-linking between the soft segments of a block copolymer can causethe copolymer to have enhanced properties, particularly with regard tocohesion and drug storage properties.

Thus, in a first aspect, the present invention provides a cross-linkedblock copolymer having drug retention properties, the block copolymerhaving hard and soft segments, characterised in that there iscross-linking between the soft segments.

Preferably, the block copolymer is an acrylic block copolymer. It isalso preferred that the block copolymer is capable of acting as anadhesive, preferably on its own, but also in conjunction with one ormore substances, such as those typically used in the manufacture oftransdermal patches.

Thus, in a preferred aspect, there is provided a block copolymer,preferably an acrylic block copolymer, comprising soft and hardsegments, that is suitable for use as an adhesive, characterised in thatthere is a degree of chemical cross-linking between the soft segments.

It will be appreciated that the term ‘drug’, as used herein, refers toany substance or compound suitable for administration via a transdermalpatch. A substance having drug retention properties is taken herein asbeing a substance capable of absorbing or adsorbing a drug. In theinstance where the substance is loaded with drug for dispensing via atransdermal patch, then it will be appreciated that such absorbanceand/or adsorbance should be at least partially reversible.

The block copolymers of the present invention are simple to manufacturein an economic fashion, and may be selected for their drug retentionand/or adhesive/cohesive properties. Accordingly, it is possible toprovide an adhesive for use with a transdermal patch which allows thedelivery of a greater amount of drug than is currently possible usingknown adhesives, as well as providing cleaner removal of used patches.

The term ‘block copolymer’, as used herein, refers to a macromoleculecomprised of two, or more, chemically dissimilar polymer structures,terminally connected together (Block Copolymers: Overview and CriticalSurvey, Noshay and McGrath, 1977). These dissimilar polymer structures,sections or segments, represent the ‘blocks’ of the block copolymer. Theblocks may generally be arranged in an A-B structure, an A-B-Astructure, or a multiblock-(A-B)_(n)-system, wherein A and B are thechemically distinct polymer segments of the block copolymer.

It is generally preferred that the block copolymer of the presentinvention is of an A-B-A structure, especially wherein one of A and B isan acrylic type polymeric unit. It will be appreciated that the presentinvention is also applicable to block copolymers which possess three, ormore different ‘blocks’, such as an A-B-C block copolymer. However, forconvenience, reference hereinafter to block copolymers will assume thatthere are only A and B sub-units, but it will be appreciated that suchreference also encompasses block copolymers having more than twodifferent sub-units, unless otherwise specified.

It will be appreciated that the properties of block copolymers are verylargely determined by the nature of the A and B blocks. Block copolymerscommonly possess both ‘hard’ and ‘soft’ segments. A ‘hard’ segment is apolymer that has a glass transition temperature (T_(g)) and/or a meltingtemperature (T_(M)) that is above room temperature, while a soft segmentis a polymer that has a T_(g) (and possibly a T_(M)) below roomtemperature. The different segments are thought to impart differentproperties to the block copolymer. Without being constrained by theory,it is thought that association of the hard segments of separate blockcopolymer units result in physical cross-links within the blockcopolymer, thereby promoting cohesive properties of the block copolymer.It is particularly preferred that the hard segments of the blockcopolymers of the present invention form such physical closeassociations.

The present invention preferably relates to acrylic block copolymers. Inacrylic block copolymers, at least one of the blocks of the blockcopolymer is an acrylic acid polymer, or a polymer of an acrylic acidderivative. The polymer may be composed of just one repeated monomerspecies. However, it will be appreciated that a mixture of monomericspecies may be used to form each of the blocks, so that a block may, initself, be a copolymer. The use of a combination of different monomerscan affect various properties of the resulting block copolymer. Inparticular, variation in the ratio or nature of the monomers used allowsproperties such as adhesion, tack and cohesion to be modulated, so thatit is generally advantageous for the soft segments of the blockcopolymer to be composed of more than one monomer species.

It is preferred that alkyl acrylates and alkyl methacrylates arepolymerised to form the soft portion of the block copolymer. Alkylacrylates and alkyl methacrylates are thought to provide properties oftack and adhesion. Suitable alkyl acrylates and alkyl methacrylatesinclude n-butyl acrylate, n-butyl methacrylate, hexyl acrylate,2-ethylbutyl acrylate, isooctyl acrylate, 2-ethylhexyl acrylate,2-ethylhexyl methacrylate, decyl acrylate, decyl methacrylate, dodecylacrylate, dodecyl methacrylate, tridecyl acrylate and tridecylmethacrylate, although other suitable acrylates and methacrylates willbe readily apparent to those skilled in the art. It is preferred thatthe acrylic block copolymer comprises at least 50% by weight of alkylacrylate or alkyl methacrylate (co) polymer.

A polar monomer is advantageously copolymerised with the alkyl acrylateor alkyl methacrylate where it is desired to enhance the drug solubilityof certain, especially hydrophilic, drugs. Suitable polar monomers whichcan be copolymerised with alkyl acrylates or alkyl methacrylates includehydroxyethyl acrylate, hydroxypropyl acrylate, vinyl pyrrolidone,acrylamide, dimethylacrylamide, acrylonitrile, diacetone acrylamide andvinyl acetate, although others will be apparent to those skilled in theart.

Diacetone acrylamide, or a combination of diacetone acrylamide and vinylacetate, is useful in the present invention. The diacetone acrylamidecomponent enables more advantageous drug loading capabilities than vinylacetate, but vinyl acetate enhances the rate of polymerisation, which isof commercial importance. In such a case, where two polar monomers areused in an adhesive, it will be appreciated that the levels of eachmonomer may be manipulated in such a way as to provide optimum drugretention and delivery.

As stated above, variation in the components of the soft segment affectsthe overall properties of the block copolymer, although the essentialfeature remains the cross-linking of the soft segments. For example,soft segments consisting essentially of diacetone acrylamide with eitherbutyl acrylate and/or 2-ethylhexyl acrylate, in approximately equalproportions, work well, and a ratio by weight of about 3:4:4 providesgood results. It is preferred that diacetone acrylamide, or other polarmonomer, such as hydroxyethyl methacrylate or vinyl acetate, be presentin no more than 50% w/w of the monomeric mix of the soft segment, asthis can lead to reduced adhesion, for example. However, where adhesionis not important, good levels of drug loading may be obtained with anexcess of polar monomer. The acrylate component may generally be variedmore freely, with good results observed with both 2-ethylhexyl acrylateand butyl acrylate together or individually, although with greaterhydrophobic side chain size, there is a slight decrease in drug loading,both for hydrophobic and hydrophilic drugs.

As noted above, ratios of the various monomers are generally preferredto be approximately equal. For adhesives, this is preferred to be with apolar component of 50% or less of the soft segment, with the apolarportion forming up to about 85% w/w, but preferably between about 50 and70% w/w. In the example above, this is about 72% (4+4) apolar to about18% (3) polar.

In general, it is preferred that the combination of monomers chosenproduces an adhesive, and that the adhesive has a combination of gooddrug loading, cohesion and adhesion, such that it is suitable for usewith a transdermal patch. When varying the monomers and their differentratios, it is preferred to retain good drug loading properties.

Prior art adhesives are generally capable of drug loading of up to about5% w/w adhesive. Block copolymers of the present invention, depending oncomposition, can often load in excess of 15%, but loading of between 5and 10% is readily obtainable. Drug loading of less than 5% isoccasionally observed, depending on the constitution and method ofpreparation of the block copolymer, but this is acceptable, especiallywhere other properties, such as cohesion, are important.

It will be appreciated that compounds with high drug retentionproperties but reduced adhesion may also be suitable as an adhesive foruse with a medical patch. Such adhesives may be appropriate for use in atransdermal patch which need only be applied for a short time or,alternatively, the adhesive may be used in combination with a furtheragent, such as an enhancer, for example polyethylene glycol, Azone™(Laurocapram, or 1-Dodecylhexahydro-2H-azepine-2-one), vitamin E orliquid paraffin, to increase its adhesive properties.

As discussed above, polymers suitable for use as the hard portion of theblock copolymer possess glass transition temperatures above roomtemperature. Suitable monomers for use in forming the hard segmentpolymer include styrene, α-methylstyrene, methyl methacrylate and vinylpyrrolidone, although other suitable monomers will be readily apparentto those skilled in the art. Styrene and polymethyl methacrylate havebeen found to be suitable for use in the formation of the hard segmentof the block copolymers of the present invention.

It is preferred that the hard portion of the block copolymer forms from3-30% w/w of the total block copolymer, particularly preferably from5-15% w/w.

The block copolymer of the present invention is one wherein the softportions contain a degree of chemical cross-linking. Such cross-linkingmay be effected by any suitable cross-linking agent. It is particularlypreferable that the cross-linking agent be in the form of a monomersuitable for incorporation into the soft segment during polymerisation.Preferably the cross-linking agent has two, or more, radicallypolymerisable groups, such as a vinyl group, per molecule of themonomer, at least one tending to remain unchanged during the initialpolymerisation, thereby to permit cross-linking of the resulting blockcopolymer.

Suitable cross-linking agents for use in the present invention includedivinylbenzene, methylene bis-acrylamide, ethylene glycoldi(meth)acrylate, ethylene glycol tetra(meth)acrylate, propylene glycoldi(meth)acrylate, butylene glycol di(meth)acrylate, ortrimethylolpropane tri(meth)acrylate, although other suitablecross-linking agents will be readily apparent to those skilled in theart. A preferred cross-linking agent is tetraethylene glycoldimethacrylate. It is preferred that the cross-linking agent constitutesabout 0.01-0.6% by weight of the block copolymer, with 0.1-0.4% byweight being particularly preferred.

Methods for the production of block copolymers from their monomericconstituents are well known. The block copolymer portions of the presentinvention may be produced by any suitable method, such as step growth,anionic, cationic and free radical methods (Block Copolymers, supra).Free radical methods are generally preferred over other methods, such asanionic polymerisation, as the solvent and the monomer do not have to bepurified.

Suitable initiators for polymerisation include polymeric peroxides withmore than one peroxide moiety per molecule. One suitable initiator hasbeen found to be ‘Perhexa MC’ (1,1′-di-teributyl-peroxy-2-methylcyclohexane, Nihon Yusi C.C.). This compound contains two tertiary butylperoxy groups which allow stepwise polymerisation of the hard and softsegments of the block copolymer. The initiator CH-50-AL (Peroxid-ChemieGmbH) has also been found to be suitable in the manufacture of compoundsof the present invention. Choice of reaction conditions is well withinthe skill of one in the art, once a suitable initiator has been chosen.

The initiator is preferably used in an amount of 0.005-0.1% by weight ofthe block copolymer, with 0.01-0.05% by weight being particularlypreferred, although it will be appreciated that the amount chosen is,again, well within the skill of one in the art. In particular, it ispreferred that the amount should not be so much as to cause instantgelling of the mix, nor so low as to slow down polymerisation and toleave excess residual monomers. A preferred level of residual monomersis below 2000 ppm. It will also be appreciated that the amount ofinitiator will vary substantially, depending on such considerations asthe initiator itself and the nature of the monomers.

The block copolymers of the present invention are preferably adhesives,particularly preferably pressure sensitive adhesives. Pressure sensitiveadhesives can be applied to a surface by hand pressure and require noactivation by heat, water or solvent. As such, they are particularlysuitable for use with transdermal patches. Block copolymer adhesives ofthe present invention are particularly suitable for use in combinationwith a transdermal patch.

A number of adhesives currently used in transdermal patches require theuse of a tackifier, to provide improved tack. The block copolymers ofthe present invention are suitable for use without a tackifier and, assuch; are particularly advantageous. However, it will be appreciatedthat the block copolymers of the present invention are also suitable foruse in combination with a tackifier, should one be required or desired.Suitable tackifiers are well known and will be readily apparent to thoseskilled in the art.

Without being constrained by theory, it is thought that the combinationof chemical cross-links between the soft segments of the copolymercombined with the, generally, hydrophobic interaction, or physicalcross-linking, between the hard portions results in a ‘matrix-like’structure. Copolymers having only physical cross-linking of the hardsegments are less able to form such a matrix. It is believed that thecombination of both forms of cross-linking of the block copolymers ofthe present invention provides both the increased internal strength(cohesion) and also the significantly improved drug storage capacitythat is observed.

Essentially, it is believed that the hard segments associate to formislands, or nodes, with the soft segments radiating from and betweenthese nodes. Where the soft segment is the B segment of an ABAstructure, then it needs to be as long as possible to permit ingress ofthe drug.

In the block copolymers of the present invention, there is a definedphysical structure in the ‘sea’ between the islands, where the softsegments are cross-linked, so that there is no necessity for extensiveintermingling of the soft segments. This results in a greater cohesionof the whole block copolymer while, at the same time, allowing shortenedsoft segment length and still having as great, or greater, distancesbetween the islands. This permits greater drug storage capacity. Evenwhere soft segment length is reduced to 50% or lower than that of theart, the adhesives still have a greater cohesion and can also bemanufactured more easily (infra).

It is thought that the ability of a copolymer adhesive to retain a drugis related to the length of the copolymer chains and the degree ofcross-linking. The improved drug storage capacity of the block copolymerof the present invention allows reduction in the length of polymerchains in comparison to other copolymers that are used as adhesives,while still providing improved drug storage. Further, shortening of thepolymer chains reduces the viscosity of the block copolymer, which isparticularly advantageous in the manufacture of the adhesive.

Thus, there is further provided a transdermal patch comprising a blockcopolymer of the present invention, the block copolymer preferably beingan adhesive.

The term ‘transdermal patch’, as used herein, is used to describe anymeans which may be applied to the skin and which may be used to delivera drug or pharmaceutical preparation onto, and preferably through, theskin layer, typically the dermis. Transdermal patches generallycomprisesa drug-impermeable backing portion and an adhesive. Theadhesive serves to stick the patch onto the skin and may also serve tocontain and deliver the drug. The transdermal patch may be any patchthat is suitable for use in combination with the block copolymeradhesive of the present invention.

It will be appreciated that the enhanced drug storage capacity of theblock copolymer of the present invention allows improvements to be madein the design of transdermal patches. For example, patches which aresmaller than those currently available can be made and which may stillsupply a therapeutically effective amount of a drug owing to the greaterdrug storage capacity and delivery of the block copolymers of thepresent invention.

The block copolymer of the present invention also allows for morestraightforward manufacturing of transdermal patches. Acrylic adhesiveswhich may be used in transdermal patches are commonly cross-linked toharden them by the use of isocyanates. However, isocyanate cross-linkingmust be carried out just prior to coating of a transdermal patch,because the cross-linking reaction begins immediately. If the adhesiveis left to cross-link for too long, then it can no longer be coated ontothe patch. However, the block copolymer of the present inventioncross-links as the solvent is removed, so that cross-linking can betimed to occur after coating, this being the preferred method.Accordingly, not only can the block copolymer easily be applied to thepatch, but the complete solution can also be stored for a period beforecoating.

Accordingly, there is also provided a process for the manufacture of across-linked block copolymer having drug retention properties, the blockcopolymer having hard and soft segments, there being cross-linkingbetween the soft segments, the process comprising polymerising themonomeric constituents of each soft segment in solution, then adding theconstituents of the hard segment to each resulting solution andpolymerising the resulting mix, followed by cross-linking by removal ofany solvent.

There is also provided such a complete solution, which providescross-linked block copolymer of the present invention on removal of thesolvent or solvent system, such as by evaporation. If the solution is tobe stored for any length of time, it may be necessary to keep thepolymer from precipitating out, and this may be achieved by known means,such as by suspending agents or shaking. It may also be necessary toselect the type of polymers that will be subject to substantially nocross-linking until the solvent is evaporated.

Suitable examples of drug-impermeable backings which may be used fortransdermal patches include films or sheets of polyolefins, polyesters,polyurethanes, polyvinyl alcohols, polyvinyl chlorides, polyvinylidenechloride, polyamides, ethylene-vinyl acetate copolymer (EVA),ethylene-ethylacrylate copolymer (EEA), vinyl acetate-vinyl chloridecopolymer, cellulose acetate, ethyl cellulose, metal vapour depositedfilms or sheets thereof, rubber sheets or films, expanded syntheticresin sheets or films, non-woven fabrics, fabrics, knitted fabrics,paper and foils. Other backings will be readily apparent to thoseskilled in the art.

Suitable drugs are typically biologically active compounds or mixture ofcompounds that have a therapeutic, prophylactic or other beneficialpharmacological or physiological effect. Examples of drugs that may beused in combination with the block copolymer of the present inventioninclude anti-arrhythmic drugs, anticoagulants, antidiabetics,antiepileptics, antifungals, antigout, antimalarials, antimuscarinicagents, antineoplastic agents, antiprotozoal agents, thyroid andantithyroid agents, anxiolytic sedatives and neuroleptics, beta blockingagents, drugs affecting bone metabolism, cardiac inotropic agents,chelating agents, antidotes and antagonists, corticosteroids, coughsuppressants, expectorants and mucolytics, dermatological agents,diuretics, gastro-intestinal agents, general and local anaesthetics,histamine H1 receptor antagonists, nitrates, vitamins, opioidanalgesics, parasympathomimetics, anti-asthma agents, muscle relaxants,stimulants and anorectics, sympathomimetics, thyroid agents, xanthines,lipid regulating agents, antiinflamatory drugs, analgesics,antiarthritic drugs, antispasmodics, antidepressants, antipsychoticdrugs, tranquillisers, narcotic antagonists, antiparkinsonism agents,cholinergic agonists, anticancer drugs, immunosupressive agents,antiviral agents, antibiotic agents, appetite suppressants, antiemetics,anticholinergics, antihistamines, antimigraine agents, coronary,cerebral or peripheral vasodilators, hormonal agents, contraceptiveagents, antithrombotic agents, diuretics, antihypertensive agents andcardiovascular drugs. Other drugs will be readily apparent to thoseskilled in the art.

Examples of specific drugs include steroids such as estradiol,levonorgestrel, norethisterone, testosterone and their esters;nitro-compounds such as nitroglycerine and isosorbide nitrates;nicotine, scopolamine; oxicam derivatives such as lornoxicam,ketoprofen, fentanyl, salbutamol, terbutaline, selegiline and clonidine,as well as pharmaceutically acceptable equivalents thereof andpharmaceutically acceptable esters and the salts of such compounds withpharmaceutically acceptable acids and bases as appropriate.

It will be appreciated that the above classes of drug, or specificdrugs, are individually contemplated for use with a transdermal patch ofthe present invention.

It will be appreciated that, while various drugs have been exemplifiedabove, some drugs are more suitable for use in transdermal deliverysystems than others. While a transdermal delivery system may deliver aquantity of a drug, this quantity may not be the optimum therapeuticdose. Essentially, any drug that can be delivered by a patch and whichdoes not substantially crystallise at levels too low to be useful isenvisaged as being useful in patches of the present invention.

It will be appreciated that the present invention also envisages the useof permeation enhancers which allow greater permeation of the drug intothe skin. Compounds suitable for use as permeation agents includecompounds containing at least one amide bond, esters of lactic acid,lactic acid, salts of lactic acid, dicarboxylicacids, salts ofdicarboxylic acids, citric acid and salts of citric acid, O-alkyl(polyoxyethyl)phosphates and esters of higher fatty acids, carboxylicacids of glycerin and ethers of polyoxyethylene and monoalcohols.Suitable enhancers include lauryl di-methanol amide, glycerinmonolaurate, glycerin triacetate and polyoxyethylene lauryl ether.

Other specific examples of permeation enhancers include PEG(polyethylene glycol), liquid paraffin, Azone and vitamin E. Inaddition, such enhancers may improve the adhesive qualities of the blockcopolymer of the invention and, where used, it may be desirable toselect an adhesive with lower adhesive properties. Alternatively, suchenhancers may be used to supplement a block copolymer having lowadhesive qualities.

The present invention also envisages the use of suitable agents toinhibit crystallisation of the drug in the adhesive. Many agents will beapparent to those skilled in the art, and polyethylene glycol isgenerally particularly effective. However, it has been found that afurther advantage of the adhesives of the present invention is thatcompounds to be delivered are generally less likely to crystallise thanthey are in prior art systems.

The present invention will now be illustrated further with reference tothe following, non-binding Examples.

EXAMPLE 1 Drug Saturation

The ability of the block copolymer of the present invention to storedrugs was compared with a polystyrene-polyisoprene-polystyrene basedadhesive (hereinafter termed ‘SIS’) used in transdermal patches(KrantonD-1101™, Shell Chemicals).

For the purpose of the comparative studies, the SIS block copolymer wasmixed with tackifier (Arkon P-100, Arakawa Chemicals, Osaka, Japan) andparaffin in the ratio 1:1.6:1.2 by weight respectively. This mixtureprovides optimised adhesive properties.

Three drugs, isosorbide mononitrate (ISMN), indomethacin and ketoprofen,were used in the present Example. Each of the drugs was mixed with eachof the two adhesives, such that a range of concentrations of drug wereobtained in each adhesive. Each adhesive/drug mix was then applied to abacking film, and the film allowed to dry. After drying, the films wereassessed for drug crystallisation.

More specifically, the compound of the present invention was dissolvedin ethyl acetate to form 39% by weight of the final solution. The SISadhesive was dissolved in chloroform, to a final concentration of 19% byweight of the final solution. Each drug was dissolved in methanol to afinal concentration of 5% by weight.

The adhesives and drug solutions were mixed together in suitableproportions such that a range of different drug concentrations wereproduced. The mix was then applied to a polyethylene terephthalate(herein abbreviated to ‘PET’) film. The solvents were evaporated off at60° C., such that thin films of adhesive containing the drug were left.All the films were then left at 50° C. for 48 hours, then roomtemperature for 48 hours. Crystal formation was assessed.

The following range of drug concentrations was chosen:

SIS adhesive: 1%, 2%, 3%, 5%, 7.5%, 10% (w/w adhesive)

Adhesive of the invention: 10%, 12.5%, 15%, 17.5%, 20% (w/w adhesive)

It was not possible to obtain concentrations of drug above 10% in theSIS adhesive. The saturation concentration of each drug was determined,which was defined as the maximum concentration of drug at which nocrystal formation was observed. The results of the experiment are shownin Table 1 below.

TABLE 1 Saturation concentration (% w/w adhesive) Adhesive of the Druginvention SIS ISMN >20%     5% Ketoprofen   17.5%   1   Indomethacin  15    <1%

It can be seen from the above Table that drug crystallised in the SISadhesive at very substantially lower concentrations than in the compoundof the invention, both ketoprofen and indomethacin being essentiallyunusable in SIS. Thus, the compound of the present invention is able toincorporate greater quantities of drug than SIS adhesive before crystalformation occurs.

EXAMPLE 2 Drug Delivery

The ability of an adhesive compound of the present invention to releaseISMN was compared to that of the SIS adhesive.

Transdermal patches were manufactured, each containing each of theadhesives in combination with ISMN. The test patches were applied to twovolunteers for 24 hours. After this time, the test patches were removed,and the residual drug levels were measured. The quantity of ISMN in astandard (control) patch was measured, to obtain a reference value.Comparison of the residual drug content of the test patches with thetotal drug content of the control patch allows the total amount of drugrelease from the patch to be determined.

More specifically, a 20% w/w solution of ISMN in methanol was prepared.The ISMN solution was mixed with a quantity of either the SIS adhesiveor the adhesive of the present invention, sufficient to obtain thedesired final drug concentration. Each adhesive-drug mix was coated ontoa 30 μm PET film (release liner). Thus, after drying, the adhesive layerhad been laminated onto a PET backing film. The films were then punchedto form circular patches of 3cm diameter.

After having been used on the patients for 24 hours, patches containingthe SIS adhesive were placed in 15 cm³ of chloroform for 24 hours todissolve the ISMN. Methanol was then used to precipitate the ISMN fromthe chloroform solution. ISMN levels were then determined by HighPressure Liquid Chromatography (HPLC).

Patches containing the adhesive of the present invention were placeddirectly in 30cm³ of methanol for 24 hours, in order to dissolve theremaining ISMN. The concentration of ISMN was determined by HPLC asabove.

In this latter case, methanol alone is sufficient to release drug fromthe adhesive of the present invention, and a chloroform step is notrequired. For comparative purposes, it has been shown that achloroform-methanol extraction of ISMN from the adhesive of the presentinvention produces identical results to that of a simple methanolextraction. Thus, the results below are directly comparable and are notaffected by the different extraction techniques used.

Drug release from the following patches was assessed, and the resultsare shown in Table 2 below.

TABLE 2 ISMN Concentration Adhesive (% w/w of the adhesive) Adhesive ofpresent invention 10% and 20% SIS adhesive 3% and 5%

It was not possible to provide more than 5% w/w of ISMN in the SISadhesive. Therefore, the relative drug release from the differentadhesives is not directly comparable. However, it is the absolute amountof drug release that is important in this case. Table 3 below shows theeffective maximum levels of drug release to the volunteer for eachadhesive.

TABLE 3 Adhesive Adhesive of Adhesive of the present the present SIS SISinvention invention (3% (5% (10% ISMN) (20% ISMN) ISMN) ISMN) Drugcontent (mg) Control patch 6.5 9.8 1.9 3.83 Residual drug content (mg)Volunteer A 4.6 7.4 1.54 2.38 Volunteer B 5.1 8.1 1.88 3.48 Total drugrelease (mg) Volunteer A 1.9 2.4 0.46 1.45 Volunteer B 1.4 1.7 0.02 0.35

From the above table, it can be seen that the total drug that may bereleased from the patch is much greater when the adhesive of the presentinvention is used. This is related to the ability of the adhesive of thepresent invention to contain a greater initial quantity of drug.Further, drug release continues from the patches of the invention afterthe test period of 24 hours.

EXAMPLE 3 Preparation of Adhesive Compounds of the Present Invention

The adhesive compound used in Examples 1 and 2 was made in a two stepsynthesis.

Step 1:

115 g of 2-ethylhexyl acrylate, 84 g of diacetone acrylamide, 115 g ofbutyl acrylate and 0.72 g tetraethylene glycol dimethacrylate weremixed, in order to obtain a homogeneous solution. The solution wasplaced in a flask, and 200 cm³ of ethyl acetate along with 200 cm³ oftoluene were added. The solution was heated to 80° C. under nitrogen,then 0.05 g of 1,1′-di-teri-butylperoxy-2-methyl cyclohexane dissolvedin 10 cm³ of ethyl acetate were added. Polymerisation was allowed toproceed for 24 hours. This step produced the soft segments.

Step 2:

After 24 hours, 45 g methyl methacrylate and 300 cm³ of toluene wereadded to the mix of Step 1. The solution was then heated to 99° C. inorder to initiate the second stage polymerisation step, which wascontinued for 12 hours.

After this time, the polymer was transferred to a bottle for cooling.The resulting solution represented a pre-crosslinked polymer, used insubsequent experiments. The average molecular weight of the polymerproduced in this way was estimated to be 358,000 Da by gel permeationchromatography.

EXAMPLE 4 Comparative Cohesion Studies

There are no industry standard tests for measuring cohesion. Cohesivestrength of the adhesives was assayed as follows.

The polymer solution of Example 3 was applied to a backing strip.Evaporation of the solvent resulted in a cross-linked adhesive compound.One end of the strip was then stuck to a glass plate, angled at 20° fromthe vertical. The rest of the strip was allowed to hang vertically. Aweight was then suspended from the free end of the strip. The time takenfor the strip to detach from the plate (i.e. for the strip and weight tofall to the ground) was measured.

More specifically, in this Example, the SIS adhesive was compared withthe adhesive compound of the present invention. The SIS adhesivecontained 5%, by weight, of ISMN, while the adhesive of the presentinvention contained 10% by weight of ISMN.

Strips of length 5 cm and width 0.6 cm, coated with one of each of theadhesive-drug mixtures, were attached to a glass plate. The totaladhesion area in each case was 0.36 cm². An 80 g weight was used. Themeasurements were taken at 25° C.

The time taken for each strip to become detached from the plate is shownin Table 4 below.

TABLE 4 Time taken to become detached Adhesive of the invention SISadhesive Sample Strip 1 >30 minutes* 7.5 minutes Sample Strip 2 >30minutes* 6.0 minutes *Detached by 24 hours

It can be seen from the above table that the adhesive of the presentinvention takes significantly longer to become detached from the glassplate, in comparison with the SIS adhesive under the same conditions.Therefore, the adhesive of the present invention has significantlyenhanced cohesive properties with respect to the SIS adhesive.

EXAMPLE 5 Effects of Variation in Monomer Composition

A number of variations of the adhesive of the invention were prepared,in order to determine the effect of variation in the composition.

5.1 Initial variants were tested for cohesion. The compositions testedare shown in Table 5 below.

TABLE 5 Composition Component A B C D E F X Y 2-ethylhexyl acrylate (g)115 115 115 115 115 115 258 258 Butyl acrylate (g) 115 115 115 115 115115 Diacetone acrylamide (g) 84 84 84 84 84 21 42 42 Ethyl acrylate (g)63 Tetraethylene glycol dimethacrylate (g) 0.72 0.72 0.36 0.48 1.5 0.480.24 0.48 Methyl methacrylate (g) 45 30 45 30 45 30 30 30 Cohesion(min's) >20 3-10 3-10 <3 N/A¹ N/A¹ <1 <1 ¹Data not available

In all the above cases, the solvents used were toluene (500 mls) andethyl acetate (200 mls). The initiator was Perhexa MC (0.05 mg) in allcases.

From the above, it can be seen that composition A represents an adhesivewith excellent cohesion. The results obtained with B and C indicate someof the variations that can be made and a suitable composition stillobtained.

Composition D contains comparatively low levels of both tetraethyleneglycol dimethacrylate and methyl methacrylate. This adhesive has loweredcohesion compared with B or C, each of which have only of these twoamounts reduced.

Compositions E and F produce gel-like polymers, which are not preferredas an adhesive suitable for use with a transdermal patch, while X and Yhad low levels of each of diacetone acrylamide, tetraethylene glycoldimethacrylate and methyl methacrylate, and produced a sticky polymerwith weak cohesion.

5.2 A number of further adhesives were made, with differentcompositions. These were tested for adhesion, cohesion and drugretention. These compositions and properties are presented in Table 6below.

TABLE 6 Composition G H I J K L M N O P Monomer¹ 2-Ethylhexyl acrylate110 110 55 55 55 55 Butyl acrylate 110 110 55 55 110 55 55 110Hydroxyethyl methacrylate 75 Diacetone acrylamide 110 55 75 75 75 75 75100 Vinyl acetate 75 37.5 37.5 40 Tetraethylene glycol dimethacrylate0.35 0.35 0.35 0.5 0.35 0.35 0.35 0.35 0.35 0.35 Methyl methacrylate 2515 15 15 15 — 15 15 15 15 Styrene 15 Initiator¹ Perhexa MC 0.09 0.140.14 0.14 0.14 0.14 0.14 0.14 0.21 0.14 Solvent² Ethyl acetate 200 200200 200 200 200 200 300 300 300 Toluene 250 250 250 250 250 250 250 350350 350 Adhesive properties³ Adhesion Slight Good Good N/A⁵ Slight GoodSlight Good N/A⁵ No adhesion Cohesion 5 10 >15 N/A⁵ 10 >15 10 >15 N/A⁵ 0Drug loading property⁴ Piroxicam 5 5 8 N/A⁵ 5 6 4 8 N/A⁵ 10 Oestradiol 88 15 N/A⁵ 6 10 <4 15 N/A⁵ >15 ¹units = grams ²units = ml ³units =minutes ⁴units = grams per 100 g of adhesive ⁵Not available

From the above, it can be seen that compositions G, H, I, K, L, M and Nshow good drug retention properties, in combination with suitablecohesive and adhesive properties. These adhesives are suitable for usein combination with transdermal patches.

Compounds J and O, which have high levels of tetraethylene glycoldimethacrylate and Perhexa MC, produced a product which gelled at thefirst stage of polymerisation. Such compounds are not suitable for useas adhesives for transdermal patches.

Compound P, with a high level of hydrophilic monomers, produced aproduct with no adhesion. This compound is unsuitable for use as anadhesive for transdermal patches, unless adhesion can be generated inthe presence of an enhancer. In any event, this compound may be suitablefor use with transdermal patches as a drug retention agent, even if anextra adhesive is necessary, owing to its great drug retention.

COMPARATIVE EXAMPLE 1 Cohesion and Drug Loading Capacitv of CommerciallyAvailable Adhesives

Two commercially available adhesives used in transdermal patches weretested for drug loading capacity, using the drugs piroxicam andestradiol. The adhesives were National Starch 837-2516 and NationalStarch 387-2052.

Each drug showed cohesion of greater than 15 minutes.

National Starch 837-2516 was able to hold 4 g of piroxicam and 4 g ofestradiol, per 100 g of adhesive.

National Starch 837-2052 was able to hold 4 g of piroxicam and 2 g ofestradiol, per 100 g of adhesive.

Thus, by comparison with Table 6 above, the National Starch adhesivesshow equivalent drug loading properties to composition M, while allother compounds of Table 6 for which drug loading was tested showedimproved drug loading with respect to the commercially availableproducts.

EXAMPLE 6 Use of Initiator CH-50-AL

Experiments were carried out using the initiator CH-50-AL, in place ofPerhexa MC. CH-50-AL is 1,1-di(tert-butylperoxy)cyclohexane, and isavailable from Peroxid-Chemie GmbH. The compositions listed in Table 7below were tested.

TABLE 7 Composition Q R Monomer¹ 2-Ethylhexyl acrylate 85 85 Butylacrylate 85 85 Diacetone acrylamide 63 63 Terraethylene glycoldimethacrylate 0.25 0.25 Methyl methacrylate 20 20 Initiator¹ CH-50-AL0.1 0.1 Solvent² First stage Ethyl acetate 150 150 Toluene 150 50 Secondstage Toluene 150 150 Temperature first stage 90 90 second stage 98 98Cohesive properties Cohesion 5 minutes >20 minutes ¹units = grams ²units= mls.

What is claimed is:
 1. An acrylic cross-linked block copolymer havinghard and soft segments, wherein there is cross-linking between the softsegments, and the block copolymer has sufficient drug retentionproperties so that, when in a composition containing an amount ofadhesive and ISMN, the composition has a saturation concentration ofISMN that is at least 10 percent on a weight to weight basis relative tothe amount of adhesive in the composition.
 2. The block copolymer ofclaim 1, wherein the block copolymer is an adhesive.
 3. The blockcopolymer of claim 1, wherein the block copolymer is an adhesive when inconjunction with one or more adhesive enhancers.
 4. The block copolymerof claim 1, which has an A-B-A structure.
 5. The block copolymer ofclaim 1, which has as A-B-A structure and wherein one of A and B is anacrylic polymeric unit.
 6. The block copolymer of claim 1, wherein thesoft portion of the block copolymer comprises monomeric units selectedfrom the group consisting of alkyl acrylates and alkyl methacrylates. 7.The block copolymer of claim 1, wherein said soft portion of said blockcopolymer comprises monomeric units selected from the group consistingof alkyl acrylates and alkyl methacrylates, and wherein said monomericunits are selected from the group consisting of n-butyl acrylate,n-butyl methacrylate, hexyl acrylate, 2-ethylbutyl acrylate, isooctylacrylate, 2-ethylhexyl acrylate, 2-ethylhexyl methacrylate, decylacrylate, decyl methacrylate, dodecyl acrylate, dodecyl methacrylate,tridecyl acrylate and tridecyl rnethacrylate and mixtures thereof. 8.The block copolymer of claim 1, wherein the block copolymer comprises anacrylic block copolymer, and the acrylic block copolymer comprises atleast 50% by weight of alkyl acrylate or alkyl methacrylate (co)polymer.9. The block copolymer of claim 1, wherein a polar monomer iscopolymerised with the alkyl acrylate or alkyl methacrylate.
 10. Theblock copolymer of claim 6, wherein a polar monomer is copolymerisedwith said alkyl acrylate or alkly methacrylate and said polar monomer isselected from hydroxyethyl acrylate, hydroxypropyl acrylate, vinylpyrrolidone, acryl amide, dimethylacrylamide, acrylonitrile, diacetoneacrylamide, vinyl acetate and mixtures thereof.
 11. The block copolymerof claim 1, wherein the block copolymer comprises an adhesive thatcontains an agent to enhance adhesive properties of the block copolymer.12. The block copolymer of claim 1, wherein the block copolymercomprises an adhesive containing an agent selected from the groupconsisting of polyethylene glycol, laurocapramii, vitamin E and liquidparaffin.
 13. The block copolymer of claim 1, which is an adhesive,wherein said adhesive properties are enhanced by a further agentselected from lauryl di-methanol amide, glycerin monolaurate, glycerintriacetate or polyoxyethylene lauryl ether.
 14. The block copolymer ofclaim 1, wherein said hard segment polymer is formed from a substanceselected from the group consisting of styrene, α-methylstyrene, methylmethacrylate, vinyl pyrrolidone and mixtures thereof.
 15. The blockcopolymer of claim 1, wherein said hard segment polymer is formed from asubstance selected from the group consisting of styrene and polymethylmethacyrylate and mixtures thereof.
 16. The block copolymer of claim 1,wherein the hard portion of the block copolymer forms from 3-30% w/w ofthe total block copolymer.
 17. The block copolymer of claim 1, whereinthe hard portion of the block copolymer forms from 5-15% w/w of thetotal block copolymer.
 18. The block copolymer of claim 1, which is apressure sensitive adhesive.
 19. A transdermal patch comprising theblock copolymer of claim
 1. 20. A transdermal patch comprising the blockcopolymer of claim 1 which is loaded with a drug selected from the groupconsisting of, anti-arrhythic drugs, anticoagulants, antidiabetics,antiepileptics, antifungals, antigout, antimalarials, antimuscarinicagents, antieoplastic agents, antiprotozoal agents, thyroid andantithyroid agents, anxiolytic sedatives and neuroleptics, beta blockingagents, drugs affecting bone metabolism, cardiac inotropic agents,chelating agents antidotes and antagonists, corticosteroids, coughsuppressants, expectorants and mucolytics, dermatological agents,diuretics, gastro-intestinal agents, general and local anesthetics,histamine H1 receptor antagonists, nitrates, vitamins, opioidanalgesics, parasympathomimetics, anti-asthma agents, muscle relaxants,stimulants and anorectics, sympathomimetics, thyroid agents, xanthines,lipid regulating agents, anti-inflammatory drugs, analgesics,antiarthritic drugs, antispasmodics, antidepressants, antipsychoticdrugs, tranquilizers, narcotic antagonists, antiparkinsonism agents,cholinergic agonists, anticancer drugs, immunosuppressive agents,antiviral agents, antibiotic agents, appetite suppressants, antiemetics,anticholinergics, antihistamines, antimigraine agents, coronary,cerebral or peripheral vasodilators, hormonal agents, contraceptiveagents, antithrombotic agents, diuretics, antihypertensive agents andcardiovascular agents.
 21. The patch of claim 20, wherein the drug isselected from the group consisting of steroids plus salts and estersthereof.
 22. The patch of claim 20, wherein the drug is selected fromthe group consisting of estradiol, levonorgestrel, norethisterone,testosterone and salts and esters thereof.
 23. The patch of claim 20,wherein the drug is selected from the group consisting ofnitro-compounds plus salts and esters thereof.
 24. The patch of claim20, wherein the drug is selected from the group consisting ofnitroglycerine, isosorbide nitrates and the salts and esters thereof.25. The patch of claim 20, wherein the drug is selected from the groupconsisting of nicotine and scopolamine and salts and esters thereof. 26.The patch of claim 20, wherein the drug is selected from the groupconsisting of oxicam derivatives plus salts and esters thereof.
 27. Thepatch of claim 20, wherein the drug is selected from the groupconsisting of lornoxicam, ketoprfen, fentanyl, salbutamol, tebutaline,selegiline and cloidine and salts and esters thereof.
 28. A process forthe manufacture of a cross-linked block copolymer having hard and softsegments, there being cross-linking between the soft segments, theprocess comprising polymerising the monomeric constituents of each softsegment in solution, said constituents including at least onecross-linking agent, then adding the constituents of the hard segment toeach resulting solution and polymerising the resulting mix, followed bycross-linking by removal of any solvent, an initiator being added beforeadding the constituents of the hard segment, wherein the block copolymerhas sufficient drug retention properties so that, when in a compositioncontaining an amount of adhesive and ISMN, the composition has asaturation concentration of ISMN that is at least 10 percent on a weightto weight basis relative to the amount of adhesive in the composition.29. The process of claim 28, wherein the block copolymer is so producedas to have the properties of a block copolymer of claim
 1. 30. Theprocess of claim 28, wherein the cross-linking agent is in the form ofat least one monomer suitable for incorporation into the soft segmentduring polymerization.
 31. The process of claim 30, wherein the at leastone cross-linking agent has two, or more, radically polymerizablegroups.
 32. The process of claim 30, wherein the at least onecross-linking agent is selected from the group consisting ofdivinyl-benzene, methylene bis-acrylamide, ethylene glycoldi(meth)acrylate, ethylene glycol tetra(meth)acrylate, propylene glycoldi(meth)acrylate, butylene glycol di(meth)acrylate, andtrimethylolpropane tri(meth)acrylate.
 33. The process of claim 30,wherein the at least one cross-linking agent is tetraethylene glycoldimethacrylate.
 34. The process of claim 30, wherein the cross-linkingagent constitutes 0.01-0.6% by weight of the block copolymer.
 35. Theprocess of claim 30, wherein the cross-linking agent constitutes0.1-0.4% by weight of the block copolymer.
 36. The process of claim 28,wherein the initiator is 1,1′-di-tert-butylperoxy-2-methylcyclohexane.37. The process of claim 28, wherein the initiator used is in an amountof 0.005-0.1% by weight of the block copolymer.
 38. The process of claim28, wherein the initiator is used in an amount of 0.01-0.05% by weight.39. The process of claim 28, wherein a polar monomer comprises up to 50%w/w of the monomers of any soft segment.
 40. The process of claim 39,wherein a polar monomer comprises in excess of 15% w/w of the monomersof any soft segment.
 41. A transdermal patch comprising the blockcopolymer of claim
 18. 42. A cross-linked block copolymer having hardand soft segments, wherein there is cross-linking between said softsegments, said soft segments comprise monomeric units selected from thegroup consisting of alkyl acrylates and alkyl niethacrylates, and saidhard segment polymer comprises at least one monomer selected from thegroup consisting of styrene, a□methylstyrene, methyl methacrylate, vinylpyrrolidone and mixtures thereof, and wherein the block copolymer hassufficient drug retention properties so that, when in a compositioncontaining an amount of adhesive and ISMN, the composition has asaturation concentration of ISMN that is at least 10 percent on a weightto weight basis relative to the amount of adhesive in the composition.43. The block copolymer of claim 42, wherein said hard segment portionof said block copolymer forms from about 3 to 30% w/w of total blockcopolymer.
 44. The block copolymer of claim 42, wherein said softsegments further comprise at least one cross-linking agent in monomericform, said cross-linking agent comprises a monomeric residue of amonomer having at least two radically polymerizable groups, and saidsoft segments are cross-linked via said cross-linking agent.
 45. Across-linked block copolymer having hard and soft segments, whereinthere is cross-linking between said soft segments, said soft segmentportion comprises monomeric units selected from the group consisting ofalkyl acrylates and alkyl methacrylates, and diacetone acrylamide is aningredient of at least one soft segment and wherein the block copolymerhas sufficient drug retention properties so that, when in a compositioncontaining an amount of adhesive and ISMN, the composition has asaturation concentration of ISMN that is at least 10 percent on a weightto weight basis relative to the amount of adhesive in the composition.46. The block copolymer of claim 45, wherein said soft segments furthercomprise at least one cross-linking agent in monomeric form, saidcross-linking agent comprises a monomeric residue of a monomer having atleast two radically polymerizable groups, and said soft segments arecross-linked via said cross-linking agent.
 47. A transdermal patchcomprising the block copolymer of claim
 42. 48. A transdermal patchcomprising the block copolymer of claim
 42. 49. An acrylic cross-linkedblock copolymer having hard and soft segments, wherein there iscross-linking between the soft segments, and the block copolymer hassufficient drug retention properties so that, when in a compositioncontaining an amount of adhesive and ketoprofen, the composition has asaturation concentration of ketoprofen that is at least 10 percent on aweight to weight basis relative to the amount of adhesive in thecomposition.
 50. The block copolymer of claim 49, wherein the blockcopolymer is an adhesive.
 51. The block copolymer of claim 49, whereinthe block copolymer is an adhesive when in conjunction with one or moreadhesive enhancers.
 52. The block copolymer of claim 49, which has anA-B-A structure.
 53. The block copolymer of claim 49, which has as A-B-Astructure and wherein one of A and B is an acrylic polymeric unit. 54.An acrylic cross-linked block copolymer having hard and soft segments,wherein there is cross-linking between the soft segments, and the blockcopolymer has sufficient drug retention properties so that, when in acomposition containing an amount of adhesive and indomethacin, thecomposition has a saturation concentration of indometlhacini that is atleast 10 percent on a weight to weight basis relative to the amount ofadhesive in the composition.
 55. The block copolymer of claim 54,wherein the block copolymer is an adhesive.
 56. The block copolymer ofclain 54, wherein the block copolymer is an adhesive when in conjunctionwith one or more adhesive enhancers.
 57. The block copolymer of claim54, which has an A-B-A structure.
 58. The block copolymer of claim 54,which has as A-B-A structure and wherein one of A and B is an acrylicpolymeric unit.
 59. A process for the manufacture of a cross-linkedblock copolymer having hard and soft segments, there being cross-linkingbetween the soft segments, the process comprising polymerising themonomeric constituents of each soft segment in solution, saidconstituents including at least one cross-linking agent, then adding theconstituents of the hard segment to each resulting solution andpolymerising the resulting mix, followed by cross-linking by removal ofany solvent, an initiator being added before adding the constituents ofthe hard segment, wherein the block copolymer has sufficient drugretention properties so that, when in a composition containing an amountof adhesive and ketoprofen, the composition has a saturationconcentration of ketoprofen that is at least 10 percent on a weight toweight basis relative to the amount of adhesive in the composition. 60.The block copolymer of claim 59, wherein the block copolymer is anadhesive.
 61. The block copolymer of claim 59, wherein the blockcopolymer is an adhesive when in conjunction with one or more adhesiveenhancers.
 62. The block copolymer of claim 59, which has an A-B-Astructure.
 63. The block copolymer of claim 59, which has as A-B-Astructure and wherein one of A and B is an acrylic polymeric unit.
 64. Aprocess for the manufacture of a cross-linked block copolymer havinghard and soft segments, there being cross-linking between the softsegments, the process comprising polymerising the monomeric constituentsof each soft segment in solution, said constituents including at leastone cross-linking agent, then adding the constituents of the hardsegment to each resulting solution and polymerising the resulting mix,followed by cross-linking by removal of any solvent, an initiator beingadded before adding the constituents of the hard segment, wherein theblock copolymer has sufficient drug retention properties so that, whenin a composition containing an amount of adhesive and indomethacin, thecomposition has a saturation concentration of indomethacin that is atleast 10 percent on a weight to weight basis relative to the amount ofadhesive in the composition.
 65. The block copolymer of claim 64,wherein the block copolymer is an adhesive.
 66. The block copolymner ofclaim 64, wherein the block copolymer is an adhesive when in conjunctionwith one or more adhesive enhancers.
 67. The block copolymer of claim64, which has an A-B-A structure.
 68. The block copolymer of claim 64,which has as A-B-A structure and wherein one of A and B is an acrylicpolymeric unit.